1. Field of the Invention
The invention relates generally to growth factors and specifically to a new member of the transforming growth factor beta (TGF-.beta.) superfamily, which is denoted, growth differentiation factor-9 (GDF-9) and methods of use as a contraceptive.
2. Description of Related Art
The transforming growth factor .beta. (TGF-.beta.) superfamily encompasses a group of structurally-related proteins which affect a wide range of differentiation processes during embryonic development. The family includes, Mullerian inhibiting substance (MIS), which is required for normal male sex development (Behringer, et al., Nature, 345: 167, 1990), Drosophila decapentaplegic (DPP) gene product, which is required for dorsal-ventral axis formation and morphogenesis of the imaginal disks (Padgett, et al., Nature, 325:81-84, 1987), the Xenopus Vg-1 gene product, which localizes to the vegetal pole of eggs ((Weeks, et al., Cell, 51:861-867, 1987), the activins (Mason, et al., Biochem, Biophys. Res. Commun., 135:957-964, 1986), which can induce the formation of mesoderm and anterior structures in Xenopus embryos (Thomsen, et al., Cell, 63:485, 1990), and the bone morphogenetic proteins (BMPs, osteogenin, OP-1) which can induce de novo cartilage and bone formation (Sampath, et al., J Biol. Chem., 265:13198, 1990). The TGF-.beta.s can influence a variety of differentiation processes, including adipogenesis, myogenesis, chondrogenesis, hematopoiesis, and epithelial cell differentiation (for review, see Massague, Cell 49:437, 1987).
The proteins of the TGF-.beta. family are initially synthesized as a large precursor protein which subsequently undergoes proteolytic cleavage at a cluster of basic residues approximately 110-140 amino acids from the C-terminus. The C-terminal regions of the proteins are all structurally related and the different family members can be classified into distinct subgroups based on the extent of their homology. Although the homologies within particular subgroups range from 70% to 90% amino acid sequence identity, the homologies between subgroups are significantly lower, generally ranging from only 20% to 50%. In each case, the active species appears to be a disulfide-linked dimer of C-terminal fragments. For most of the family members that have been studied, the homodimeric species has been found to be biologically active, but for other family members, like the inhibins (Ling, et al., Nature, 321:779, 1986) and the TGF-.beta.s (Cheifetz, et al., Cell, 48:409, 1987), heterodimers have also been detected, and these appear to have different biological properties than the respective homodimers.
The inhibins and activins were originally purified from follicular fluid and shown to have counteracting effects on the release of follicle-stimulating hormone by the pituitary gland. Although the mRNAs for all three inhibin/activin subunits (a, .beta.A and .beta.B) have been detected in the ovary, none of these appear to be ovary-specific (Meunier, et al., Proc.Natl.Acad.Sci. USA, 85:247, 1988). MIS has also been shown to be expressed by granulosa cells and the effects of MIS on ovarian development have been documented both in vivo in transgenic mice expressing MIS ectopically (Behringer, supra) and in vitro in organ culture (Vigier, et al., Development, 100:43, 1987).
Identification of new factors that are tissue-specific in their expression pattern will provide a greater understanding of that tissue's development and function.